This invention is directed to pyrimidine and pyridine-based compounds which act as inhibitors of JAK. This invention is also directed to pharmaceutical compositions containing the pyrimidine and pyridine-based compounds and methods of using the compounds or compositions to treat a condition mediated at least in part by JAK activity. The invention is also directed to methods of making the compounds described herein.
Janus tyrosine kinases (JAKs) are a small family of structurally and functionally related non-receptor, cytoplasmic protein tyrosine kinases, including JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAKs play pivotal roles in the initiation of cytokine-triggered signaling events by signal transducers and activators of transcriptions (STATs) via tyrosine phosphorylation. JAK-mediated tyrosine phosphorylations of cytokine receptors and STATs are the important signal transduction pathways used by many cytokines, growth factors, and interferons. Upon phosphorylation, the STATs dimerize and translocate to the nucleus where they can then induce transcription of the corresponding cytokine-responsive genes. This association with relevant cytokine signaling pathways makes JAK3 an important target for therapeutic intervention in the treatment of autoimmune disorders, inflammatory diseases, cell proliferative disorder and organ transplant rejection such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, asthma and acute myeloid leukemias (AML).
JAK-3 in particular plays an essential role in the function of lymphocytes, macrophages and mast cells. The compounds that inhibit JAK-3 can be therapeutically useful in treatment of, leukemia, lymphoma where JAK3 is hyperactivated. JAK3 inhibition will be useful as immunosuppressive agent for treatment of chronic and/or acute organ transplant and autoimmune diseases such as rheumatoid arthritis, Type 1 diabetes, systemic lupus, multiple sclerosis, Crohn's disease and inflammatory diseases such as, asthma, psoriasis, chronic obstructive pulmonary disease.
An important feature of JAK3 is that it specifically associates with the common cytokine receptor gamma (γ) chain (cc) which is a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Unlike the other JAK family members, that are more widely expressed in many mammalian tissues, JAK3 expression seems to be mainly limited to the endoplasmic membranes of hematopoietic cells.
The pivotal roles in signaling through the gamma chain of γc containing cytokine receptors cytokine receptors and its limited expression and unique tissue distribution make JAK3 an attractive therapeutic target relative to the other JAK family members to manage the abnormal cytokine activities implicated in many cancer cells and inflammatory lymphocytes.
In the relatively young field of Janus kinase inhibition, Pfizer has already progressed their JAK3 inhibitor, Tasocitinib (CP-690,550), into Phase III clinical trials for acute rejection in kidney transplant patients. Other JAK3 inhibitors have been reported, such as the non-selective (within JAK family) but very potent tetracyclic pyridone 2, reported by Merck. Aventis has published an oxindole JAK3 inhibitor that shows good enzymatic selectivity vs JAK2. However, this oxindole inhibitor also shows very strong inhibition vs a panel of CDK kinases. Vertex has described aza indoles as JAK inhibitors (WO2005/95400). AstraZeneca has published quinoline 3-carboxamides as JAK 3 inhibitors (WO2002/92571) and other compounds for inhibition of all JAKs for the treatment of cancer (WO2008/135786).
Several mutated forms of JAK2 have been identified in a variety of disease settings, for example translocations resulting in the fusion of the JAK2 kinase domain with an oligomerization domain, TEL-JAK2, Bcr-JAK2 and PCM1-JAK2 have been implicated in the pathogenesis of various hematological malignancies (SD Turner and Alesander DR, Leukemia, 2006, 20, 572-582). Recently a unique mutation encoding a valine to phenylalanine substitution in JAK2 was detected in a significant number of myeloproliferative diseases such as polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis patients.
Constitutive activation of the STAT family, in particular STAT3 and STAT5 have been detected in a wide range of cancers and hyperproliferative diseases (Haura et al, Oncology, 2005, 2(6), 315-324). Further, aberrant activation of the JAK/STAT pathway provides an important proliferative and/or anti-apoptotic drive downstream of many kinases (e.g. Flt3, EGFR) whose constitutive activation have been implicated as key drivers in a variety of cancers and hyperproliferative disorders. Potent and specific inhibitors of JAK1 and JAK2 will be useful in the treatment of cancers including multiple myeloma, prostate, breast and lung cancer, B-cell Chronic Lymphocytic Leukemia, metastatic melanoma, multiple myeloma, and hepatoma.
While progress has been made in this field, there remains a need in the art for compounds that inhibit JAK kinase, as well as for methods for treating conditions in a patient, such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, asthma, acute myeloid leukemias (AML) and/or inflammation that can benefit from such inhibition. Moreover, the availability of compounds that selectively inhibit one of these kinases as compared to other kinases would also be desirable. The present invention satisfies this and other needs.